title: KITLG mutations cause familial progressive hyper- and hypopigmentation.
abstract: Familial progressive hyper- and hypopigmentation (FPHH) is thought to be an autosomal dominant disorder with reduced penetrance. Clinical signs consist of progressive diffuse, partly blotchy hyperpigmented lesions, multiple café-au-lait spots, intermingled with scattered hypopigmented-appearing maculae, and lentigines. FPHH is distinct from familial progressive hyperpigmentation (FPH), in which no hypopigmented features are present, and which is phenotypically and histologically closer to Dyschromatosis Universalis Hereditaria 2 (DUH2). It also differs from the Legius syndrome, characterized by familial café-au-lait spots and skin fold freckling, caused by mutations in SPRED1. We performed a genome-wide linkage analysis in seven families with FPHH, and identified linkage on 12q21.12-q22, which overlaps with the DUH2 locus. We investigated whether KITLG in the locus is mutated in FPHH. We discovered three different mutations in four families. A reported FPH substitution was observed in two FPHH families, and two, to our knowledge, previously unreported substitutions, p.Val33Ala and p.Thr34Pro, cosegregated with FPHH in two separate families. All three mutations were located in a conserved β-strand in KITLG, suggesting its important role in the activation of the KITLG receptor c-Kit. In aggregate, mutations in a single gene cause various pigmentation disorders: FPH, FPHH, and likely DUH2. Therefore, KITLG is an important modulator of skin pigmentation.
authors.affiliation: Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Amyere
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogt
authors.forename: Joe
authors.initials: J
authors.lastname: Hoo
authors.forename: Flemming
authors.initials: F
authors.lastname: Brandrup
authors.forename: Anette
authors.initials: A
authors.lastname: Bygum
authors.forename: Laurence
authors.initials: L
authors.lastname: Boon
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D018628:Gene Dosage; D008040:Genetic Linkage; D006801:Humans; D017495:Hyperpigmentation / Q000235:genetics*; D017496:Hypopigmentation / Q000235:genetics*; D019656:Loss of Heterozygosity; D009154:Mutation; D010766:Phosphorylation; D019089:Stem Cell Factor / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
chemical_list: D019089:Stem Cell Factor